TY - JOUR
T1 - Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity
AU - Shi, Hao
AU - Munk, Alexander
AU - Nielsen, Thomas S.
AU - Daughtry, Morgan R.
AU - Larsson, Louise
AU - Li, Shize
AU - Høyer, Kasper F.
AU - Geisler, Hannah W.
AU - Sulek, Karolina
AU - Kjøbsted, Rasmus
AU - Fisher, Taylor
AU - Andersen, Marianne M.
AU - Shen, Zhengxing
AU - Hansen, Ulrik K.
AU - England, Eric M.
AU - Cheng, Zhiyong
AU - Højlund, Kurt
AU - Wojtaszewski, Jørgen F.P.
AU - Yang, Xiaoyong
AU - Hulver, Matthew W.
AU - Helm, Richard F.
AU - Treebak, Jonas T.
AU - Gerrard, David E.
N1 - Funding Information:
The authors would like to thank Prof. Thomas Mandrup-Poulsen, University of Copenhagen, and Dr. LeBris S. Quinn for constructive comments during the manuscript preparation. Support for this study was provided by the Novo Nordisk Foundation Center for Basic Metabolic Research. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen that is partially funded by an unrestricted donation from the Novo Nordisk Foundation, http://metabol.ku.dk). JTT was supported by the Novo Nordisk Foundation (Excellence Project Award; NNF14OC0009315 ), by the Danish Council for Independent Research (Research Project Grant; DFF-4004-00235 ), and by the European Foundation for the Study of Diabetes (EFSD/Lilly Research Fellowship). JFPW was supported by the Novo Nordisk Foundation (NNF 160C0023046 ) and The Danish Medical Research Council ( DFF-6110-00498B ).
Funding Information:
The authors would like to thank Prof. Thomas Mandrup-Poulsen, University of Copenhagen, and Dr. LeBris S. Quinn for constructive comments during the manuscript preparation. Support for this study was provided by the Novo Nordisk Foundation Center for Basic Metabolic Research. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen that is partially funded by an unrestricted donation from the Novo Nordisk Foundation, http://metabol.ku.dk). JTT was supported by the Novo Nordisk Foundation (Excellence Project Award; NNF14OC0009315), by the Danish Council for Independent Research (Research Project Grant; DFF-4004-00235), and by the European Foundation for the Study of Diabetes (EFSD/Lilly Research Fellowship). JFPW was supported by the Novo Nordisk Foundation (NNF 160C0023046) and The Danish Medical Research Council (DFF-6110-00498B).
Publisher Copyright:
© 2018 The Authors
PY - 2018/5
Y1 - 2018/5
N2 - Objective: Given that cellular O-GlcNAcylation levels are thought to be real-time measures of cellular nutrient status and dysregulated O-GlcNAc signaling is associated with insulin resistance, we evaluated the role of O-GlcNAc transferase (OGT), the enzyme that mediates O-GlcNAcylation, in skeletal muscle. Methods: We assessed O-GlcNAcylation levels in skeletal muscle from obese, type 2 diabetic people, and we characterized muscle-specific OGT knockout (mKO) mice in metabolic cages and measured energy expenditure and substrate utilization pattern using indirect calorimetry. Whole body insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique and tissue-specific glucose uptake was subsequently evaluated. Tissues were used for histology, qPCR, Western blot, co-immunoprecipitation, and chromatin immunoprecipitation analyses. Results: We found elevated levels of O-GlcNAc-modified proteins in obese, type 2 diabetic people compared with well-matched obese and lean controls. Muscle-specific OGT knockout mice were lean, and whole body energy expenditure and insulin sensitivity were increased in these mice, consistent with enhanced glucose uptake and elevated glycolytic enzyme activities in skeletal muscle. Moreover, enhanced glucose uptake was also observed in white adipose tissue that was browner than that of WT mice. Interestingly, mKO mice had elevated mRNA levels of Il15 in skeletal muscle and increased circulating IL-15 levels. We found that OGT in muscle mediates transcriptional repression of Il15 by O-GlcNAcylating Enhancer of Zeste Homolog 2 (EZH2). Conclusions: Elevated muscle O-GlcNAc levels paralleled insulin resistance and type 2 diabetes in humans. Moreover, OGT-mediated signaling is necessary for proper skeletal muscle metabolism and whole-body energy homeostasis, and our data highlight O-GlcNAcylation as a potential target for ameliorating metabolic disorders.
AB - Objective: Given that cellular O-GlcNAcylation levels are thought to be real-time measures of cellular nutrient status and dysregulated O-GlcNAc signaling is associated with insulin resistance, we evaluated the role of O-GlcNAc transferase (OGT), the enzyme that mediates O-GlcNAcylation, in skeletal muscle. Methods: We assessed O-GlcNAcylation levels in skeletal muscle from obese, type 2 diabetic people, and we characterized muscle-specific OGT knockout (mKO) mice in metabolic cages and measured energy expenditure and substrate utilization pattern using indirect calorimetry. Whole body insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique and tissue-specific glucose uptake was subsequently evaluated. Tissues were used for histology, qPCR, Western blot, co-immunoprecipitation, and chromatin immunoprecipitation analyses. Results: We found elevated levels of O-GlcNAc-modified proteins in obese, type 2 diabetic people compared with well-matched obese and lean controls. Muscle-specific OGT knockout mice were lean, and whole body energy expenditure and insulin sensitivity were increased in these mice, consistent with enhanced glucose uptake and elevated glycolytic enzyme activities in skeletal muscle. Moreover, enhanced glucose uptake was also observed in white adipose tissue that was browner than that of WT mice. Interestingly, mKO mice had elevated mRNA levels of Il15 in skeletal muscle and increased circulating IL-15 levels. We found that OGT in muscle mediates transcriptional repression of Il15 by O-GlcNAcylating Enhancer of Zeste Homolog 2 (EZH2). Conclusions: Elevated muscle O-GlcNAc levels paralleled insulin resistance and type 2 diabetes in humans. Moreover, OGT-mediated signaling is necessary for proper skeletal muscle metabolism and whole-body energy homeostasis, and our data highlight O-GlcNAcylation as a potential target for ameliorating metabolic disorders.
KW - Epigenetic regulation of Il15 transcription
KW - Insulin sensitivity
KW - N-acetyl-D-glucosamine
KW - O-GlcNAc signaling
KW - Tissue cross talk
KW - Type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85042919326&partnerID=8YFLogxK
U2 - 10.1016/j.molmet.2018.02.010
DO - 10.1016/j.molmet.2018.02.010
M3 - Journal article
C2 - 29525407
AN - SCOPUS:85042919326
SN - 2212-8778
VL - 11
SP - 160
EP - 177
JO - Molecular Metabolism
JF - Molecular Metabolism
ER -